Extreme variability of clinical symptoms among sibs in a MELAS family correlated with heteroplasmy for the mitochondrial A3243G mutation

Vries, Daniëlle de; Wijs, Ilse de; Ruitenbeek, W.; Begeer, J. H.; Smit, P.; Bentlage, H.A.C.M.; Oost, Bernard van

doi:10.1016/0022-510x(94)90014-0

Cited by 45 publications

(28 citation statements)

References 29 publications

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“…Accordingly, histology and clinical progression did not differ. The biochemical consequences of the A3243G mutation in the renal carcinoma tissue are in agreement with the decreased activity of the mitochondrial-and nuclear-encoded complex I and IV reported in muscle biopsy and fibroblasts of patients with MELAS syndrome carrying the A3243G mutation (de Vries et al, 1994;Wilichowski et al, 1998;Pronicki et al, 2002). Our findings indicate that the biochemical changes caused by the pathogenic A3243G mutation are not dependent on tissue type and therefore, it seems to be a general cellular compensatory mechanism.…”

Section: Discussionsupporting

confidence: 81%

Mitochondrial DNA mutations in renal cell carcinomas revealed no general impact on energy metabolism

et al. 2006

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Previously, renal cell carcinoma tissues were reported to display a marked reduction of components of the respiratory chain. To elucidate a possible relationship between tumourigenesis and alterations of oxidative phosphorylation, we screened for mutations of the mitochondrial DNA (mtDNA) in renal carcinoma tissues and patient-matched normal kidney cortex. Seven of the 15 samples investigated revealed at least one somatic heteroplasmic mutation as determined by denaturating HPLC analysis (DHPLC). No homoplasmic somatic mutations were observed. Actually, half of the mutations presented a level of heteroplasmy below 25%, which could be easily overlooked by automated sequence analysis. The somatic mutations included four known D-loop mutations, four so far unreported mutations in ribosomal genes, one synonymous change in the ND4 gene and four nonsynonymous base changes in the ND2, COI, ND5 and ND4L genes. One renal cell carcinoma tissue showed a somatic A3243G mutation, which is a known frequent cause of MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episode) and specific compensatory alterations of enzyme activities of the respiratory chain in the tumour tissue. No difference between histopathology and clinical progression compared to the other tumour tissues was observed. In conclusion, the low abundance as well as the frequently observed low level of heteroplasmy of somatic mtDNA mutations indicates that the decreased aerobic energy capacity in tumour tissue seems to be mediated by a general nuclear regulated mechanism.

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Section: Discussionsupporting

confidence: 81%

Mitochondrial DNA mutations in renal cell carcinomas revealed no general impact on energy metabolism

et al. 2006

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“…Investigation of mtDNA in the pa tients muscle revealed no mtDNA depletion, large dele tions, or point mutations, which are frequently associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS, position 3248); myo clonic epilepsy and ragged red fiber disease (position « Mim1 ment, and we found a norm al complex I activity in fibroblasts of the second case. 19 There are previous reports on heterogeneous tis sue expression of OXPHOS defects in mitochondrial encephalomyopathies.20*22 In some cases, this was associated w ith mtDNA depletion21 or the MELAS 3243 m u tatio n , 22 Both m utations were excluded in our patient. We examined fibroblasts of 10 other pa tients w ith combined complex I and TV defects in muscle tissue, including some previously reported,5* 20 and found only in one case a complex IV defect.…”

Section: Neurology 1996;47:243-248mentioning

confidence: 79%

Lethal infantile mitochondrial disease with isolated complex I deficiency in fibroblasts but with combined complex I and IV deficiencies in muscle

Bentlage

Wendel²,

Schägger³

et al. 1996

Neurology

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A 2-month-old boy died of a lethal infantile mitochondrial disease with severe lactic acidosis and involvement of the CNS. Histochemical analysis of skeletal muscle showed that cytochrome c oxidase staining was lacking in all muscle fibers but was present in arterioles. Ragged red fibers were not seen, but some fibers showed excessive staining for succinate dehydrogenase. Biochemical analysis revealed a combined complex I and IV deficiency in skeletal muscle but only a complex I deficiency in his fibroblasts. Two-dimensional native SDS electrophoresis confirmed these enzymatic findings at the protein level. Analysis of mitochondrial translation products in fibroblasts revealed no abnormalities, and analysis of mitochondrial DNA in muscle showed no depletion, large-scale deletions, or frequently occurring point mutations. We conclude that this disease must have been the result of either a nuclear DNA mutation in a gene controlling the expression or assembly of both complex I and the muscle-specific isoform of complex IV or, alternatively, a heteroplasmic point mutation in a mitochondrial tRNA, which codon is used more often by mtDNA encoded subunits of complex I than by mtDNA encoded subunits of complex IV. A different degree of heteroplasmy in skeletal muscle and fibroblasts would then explain the curious heterogeneous tissue expression of defects in this patient.NEUROLOGY 1996;47: 243-248

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“…We investigated the A3243G mutation, 7 which is usually responsible for syndromic deafness, because hearing loss can be isolated at the onset of the disease.…”

Section: Methodsmentioning

confidence: 99%

“…The severity of the disease was clearly related to the amount of mutation, as described previously. 7 The proband consulted for an evolving deafness at the age of 25. The onset was in the second decade and the degree of hearing impairment was mild.…”

Section: Screening For A1555g Trnaser(ucn) and Trnaleu(uur) Gene Mutmentioning

confidence: 99%

Whole mitochondrial genome screening in maternally inherited non-syndromic hearing impairment using a microarray resequencing mitochondrial DNA chip

et al. 2007

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Extreme variability of clinical symptoms among sibs in a MELAS family correlated with heteroplasmy for the mitochondrial A3243G mutation

Cited by 45 publications

References 29 publications

Mitochondrial DNA mutations in renal cell carcinomas revealed no general impact on energy metabolism

Mitochondrial DNA mutations in renal cell carcinomas revealed no general impact on energy metabolism

Lethal infantile mitochondrial disease with isolated complex I deficiency in fibroblasts but with combined complex I and IV deficiencies in muscle

Whole mitochondrial genome screening in maternally inherited non-syndromic hearing impairment using a microarray resequencing mitochondrial DNA chip

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